Metastatic melanoma is a highly lethal human malignancy. Despite advances in the field, the molecular genetics of melanoma has not been fully characterized. The Cancer Genome Atlas reports high mutational load for melanoma. Identification of 'driver' genes and novel therapeutics remain as a major focus. Notably, there is a need to classify melanomas based on molecular signatures that has therapeutic relevance. Our main goal is to bring in new treatments to the therapeutic arena for melanoma and stratify patients for treatment based on genetic profiles. We identified FBXW7 mutations as a novel genetic event via exome sequencing of metastatic melanomas. FBXW7 is a tumor suppressor gene that encodes a member of the F-box protein family. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination and regulates a network of proteins with central roles in cell division, cell growth and differentiation. The substrates of FBXW7 include well-characterized oncoproteins, one of which is NOTCH1. Screening of melanoma samples revealed missense and nonsense mutations in FBXW7, some of which were recurrent. We found that silencing of FBXW7 in human melanoma cell lines result in elevated NOTCH1 levels. Moreover, we showed that xenograft tumors with FBXW7 down regulation respond to NOTCH signaling inhibition. In this proposal, we aim to study the impact of FBXW7 mutations found in human melanoma and the therapeutic benefit of NOTCH1 inhibition in this setting. The studies in this proposal are designed to expand our knowledge regarding genetic events that influence melanoma development and metastasis with the goal of identifying novel targets for future mechanism-driven clinical trials. The ultimate goal of these studies is to translate knowledge gained from molecular studies into tools that can be used in clinical decision-making.